Abstract The Center for Cancer Systems Pharmacology (CCSP) constructs and applies network-level computational models to understand mechanisms of drug response, resistance and toxicity for targeted small molecule drugs and immune checkpoint inhibitors (ICIs). We hypothesize that improved understanding of fundamental cell signaling pathways and interactions between cancer and immune cells will result in greater efficacy while minimizing toxicity. Intrinsic and acquired drug resistance pose the primary challenges to broader application of all cancer therapies. These goals are be accomplished by translating findings from the bedside to the bench and then back to the bedside focusing on melanoma, a type of cancer in which both ICIs and targeted drugs are effective, as well as triple negative breast cancer, and brain cancers (GBM). In this supplement, we will develop, validate and apply these innovative pharmacological concepts and instantiate these in practical form using computational models in Alzheimer's disease and related dementias. We have discovered a novel mechanism of neuronal death evoked by cytoplasmic dsRNA, which can trigger a type I interferon (IFN-I) response, in the brains of a subset of patients with Alzheimer's disease and Frontotemporal dementia. In a human neural cell in vitro model, we recapitulate the induction of IFN-I signaling and neuronal death by cytoplasmic dsRNA in a dose dependent manner. FDA-approved JAK inhibitors reverse neuronal death whereas other JAK inhibitors do not reverse neuronal death in spite of inhibiting STAT1 phosphorylation. This drug repurposing opportunity for Alzheimer's disease will be enhanced with a better understanding of the critical kinases that are mediating neuronal rescue and a better understanding of the elements of the IFN-I response in human brains to develop biomarkers that faithfully represent this subtype of neuroinflammation. We will also create and distribute new measurement and software methods to promote systems pharmacology in the area of neurodegenerative disease biology. Aim 1, linked to the Systems Pharmacology Core (Aim 2) and Project 3 of the parent grant, will measure and model cell type-specific signaling through chemoproteomics that contribute to the efficacy of JAK inhibitors to rescue neuronal death evoked by cytoplasmic dsRNA, in order to develop improved therapeutic strategies for patients. Aim 2, linked to the Systems Pharmacology Core and Project 2 of the parent grant, will measure and model the microenvironment around cytoplasmic dsRNA in human brains with Alzheimer's and Frontotemporal dementia using a range of innovative, highly- multiplexed assays for innate immune activation, with a particular emphasis on IFN-I signaling and stress granule composition. These efforts will coordinate with the Outreach Core of the parent grant to ensure curation and distribution of Center data according to FAIR standards.